Implementation of Time-Averaged Restraints with UNRES Coarse-Grained Model of Polypeptide Chains

Time-averaged restraints
from nuclear magnetic resonance (NMR)
measurements have been implemented in the UNRES coarse-grained model
of polypeptide chains in order to develop a tool for data-assisted
modeling of the conformational ensembles of multistate proteins, intrinsically
disordered proteins (IDPs) and proteins with intrinsically disordered
regions (IDRs), many of which are essential in cell biology. A numerically
stable variant of molecular dynamics with time-averaged restraints
has been introduced, in which the total energy is conserved in sections
of a trajectory in microcanonical runs, the bath temperature is maintained
in canonical runs, and the time-average-restraint-force components
are scaled up with the length of the memory window so that the restraints
affect the simulated structures. The new approach restores the conformational
ensembles used to generate ensemble-averaged distances, as demonstrated
with synthetic restraints. The approach results in a better fitting
of the ensemble-averaged interproton distances to those determined
experimentally for multistate proteins and proteins with intrinsically
disordered regions, which puts it at an advantage over all-atom approaches
with regard to the determination of the conformational ensembles of
proteins with diffuse structures, owing to a faster and more robust
conformational search.